Genetic and pharmacological reduction of CDK14 mitigates α-synuclein pathology in human neurons and in rodent models of Parkinson’s disease

Abstract

Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons (DaNs) and the abnormal accumulation of alpha-Synuclein (a-Syn) protein. Currently, no treatment can slow nor halt neurodegeneration. Multiplications and mutations of the a-Syn gene (SNCA) cause PD-associated syndromes and animal models that overexpress a-Syn replicate several features of PD. Decreasing total a-Syn levels, therefore, is an attractive approach to slow down neurodegeneration in patients with a 'synucleinopathy'. We previously performed a genetic screen for modifiers of a-Syn levels, and found CDK14, a kinase of largely unknown function as a regulator of a-Syn. To test the potential therapeutic effects of CDK14 reduction in PD, we decreased Cdk14 in two mouse models of synucleinopathy. We found that reduction of Cdk14 mitigated neuropathological and neurobehavioral sequelae associated with a-Syn overexpression. We further validated these findings in PD patient neurons. Finally, we leveraged the recent discovery of a covalent inhibitor of CDK14 to determine whether this target is pharmacologically tractable ex vivo. We found that in both mouse and human neurons, CDK14 inhibition decreases total and pathologically aggregated a-Syn. In summary, we suggest that CDK14 represents a novel therapeutic target for PD-associated synucleinopathy.